Discovery of Small Molecules for Repressing Cap-Independent Translation of Human Vascular Endothelial Growth Factor (hVEGF) as Novel Antitumor Agents

Journal of Medicinal Chemistry
Shi-Ke WangTian-Miao Ou

Abstract

Angiogenesis is important in tumorigenesis and tumor progression. Human vascular endothelial growth factor (hVEGF) is an angiogenic growth factor that plays a crucial role in tumor progression. The G-rich region within the 5'-untranslated regions (5'-UTR) of hVEGF-A mRNA can form a "switchable" RNA G-quadruplex structure that is essential for a cap-independent translation initiation. We screened our small-molecule library for binders of this G-tract. One novel quinazoline derivative, compound 1, showed a significant specific interaction with the G-tract and destabilized the G-quadruplex structure. The results of cellular experiments revealed that compound 1 down-regulated hVEGF-A translation and significantly impeded tumor cells migration. We also found that compound 1 exhibited tumor-inhibiting activity in MCF-7 xenograft tumors, which might be related to its ability to reduce hVEGF expression. These findings present a new strategy of hVEGF-A translational control in which small molecules interact with G-quadruplex structure in the 5'UTR.

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Citations

Feb 24, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tong CheShuo-Bin Chen
Aug 14, 2018·Nucleic Acids Research·Brittany S MorganAmanda E Hargrove
Nov 28, 2017·Organic & Biomolecular Chemistry·Zi-Qi LiChun-Qiong Zhou
Feb 18, 2021·Cell Chemical Biology·Pauline LejaultDavid Monchaud
Apr 7, 2021·Cell Chemical Biology·Martina Zafferani, Amanda E Hargrove
Jul 3, 2021·Cancers·Victoria Sanchez-MartinJose Antonio Garcia-Salcedo

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